Enzymatic Reduction of Chloramphenicol and Nitrosochloramphenicol by Rat Liver Microsomal Preparations

Lim, Lori O.; Yunis, Adel A.

doi:10.1159/000137830

Cited by 7 publications

(1 citation statement)

References 6 publications

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“…These organelles, known to play a major role in cellular aerobic metab olism, were first described to play a role in the formation of nitroaromatic free radical intermediates, strictly under anaerobic con ditions [10], More recently, mitochondria isolated from rat brain and incubated under aerobic conditions were reported to contain a nitroreductase activity capable of converting the anti-schistosomal agent niridazole and other aromatic nitro compounds into the hydroxylamine metabolites [11]. Moreover, mitochondria isolated from rat liver were shown to possess a nitroreductase activity which is associated with their outer mem brane and which catalyzes the reduction of nitrofuran derivatives to generate nitro anion radicals [12], As part of a study to investigate the bio chemical mechanism of chloramphenicol toxicity, we have been examining a micro somal nitro reduction of this and some other nitro compounds [13,14]. Since chloram phenicol reacts mainly at the mitochondrial level we have studied the presence of a ni troreductase activity in intact rat liver mito chondria.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Mitochondrial <i>p</i>-Dinitrobenzene Reductase Activity in Rat Liver

Abou‐Khalil¹,

Abou-Khalil²,

Yunis³

1985

Pharmacology

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Nitroreductase activity has been known to occur under nitrogen atmosphere in the cytosolic and microsomal fractions of liver homogenate. The present study describes a new localisation for a subcellular nitro reduction activity which occurs in liver mitochondria under aerobic conditions. Mitochondria were isolated from rat liver and assayed for their capacity to reduce certain nitro compounds by measuring spectrophotometrically both the appearance of amino compounds and the consumption of NADH. Intact mitochondria were found to possess a p-dinitrobenzene (p-DNB) reductase activity which was reduced by over 50% upon addition of detergent. The activity was destroyed by heat, and was present at only 20% in the microsomal fraction. It was strictly NADH-dependent, while only little or no activity occurred with NADPH or other oxidative substrates. Moreover, this nitro reduction was protein concentration- and time-dependent reaching a plateau after 20 min, and was also inhibited by thiol reagents. Assayed under the same conditions, rat liver mitochondria showed about 15% activity with o-DNB and m-DNB, while there was less than 5% activity with a series of p-nitro compounds including chloramphenicol. The presence of a nitroreductase activity in liver mitochondria, although shown here to be restricted to p-DNB, may have important implications regarding cytotoxicity from nitro compounds.

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Section: Introductionmentioning

confidence: 99%

Identification of a Mitochondrial <i>p</i>-Dinitrobenzene Reductase Activity in Rat Liver

Abou‐Khalil¹,

Abou-Khalil²,

Yunis³

1985

Pharmacology

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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DNA damage in intact cells induced by bacterial metabolites of chloramphenicol

et al. 1988

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Four chloramphenicol (CAP) metabolites known to be produced by intestinal bacteria were examined with respect to their capacity to induce DNA damage in intact cells. The induction of DNA single-strand breaks in Raji cells, activated human lymphocytes, and human marrow cells was assayed by the alkaline elution technique. One of the four compounds tested, dehydro-CAP, was capable of inducing DNA single-strand breaks in all three cell systems at concentrations of 10(-4) M. This effect is comparable to that observed previously with nitroso-CAP, the nitroreduction intermediate of CAP. The nitroreduction of dehydro-CAP by human bone marrow cell homogenate was detected by the production of the corresponding amino derivative amounting to 5.6 X 10(-5) M from 2 X 10(-3) M substrate under aerobic conditions. In sharp contrast, nitroreduction of CAP by bone marrow could not be demonstrated. The genotoxicity of dehydro-CAP, its relative stability compared to the nitroso-CAP, and its nitroreducibility by bone marrow suggest that this bacterial metabolite of CAP may play a key role as a mediator of aplastic anemia in the predisposed host.

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Enzymatic Reduction of Chloramphenicol and Nitrosochloramphenicol by Rat Liver Microsomal Preparations

Cited by 7 publications

References 6 publications

Identification of a Mitochondrial <i>p</i>-Dinitrobenzene Reductase Activity in Rat Liver

Identification of a Mitochondrial <i>p</i>-Dinitrobenzene Reductase Activity in Rat Liver

Principles of Drug Metabolism

DNA damage in intact cells induced by bacterial metabolites of chloramphenicol

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